Impact of Sleep and Sleep Disturbances on Obesity and Cancer (1)

“Sleep has recently been recognized as a critical determinant of energy balance, regulating restoration and repair of many of the physiological and psychological processes involved in modulating energy intake and utilization. Emerging data indicate that sleep can now be added to caloric intake and physical activity as major determinants of energy balance with quantitative and qualitative imbalances leading to under- or overnutrition and associated comorbidities. Considerable research is now focused on disorders of sleep and circadian rhythm and their contribution to the worldwide obesity pandemic and the associated comorbidities of diabetes, cardiovascular disease, and cancer. In addition to having an impact on obesity, sleep and circadian rhythm abnormalities have been shown to have significant effects on obesity-associated comorbidities, including metabolic syndrome, premalignant lesions, and cancer. In addition to the observation that sleep disturbances are associated with increased risk for developing cancer, it has now become apparent that sleep disturbances may be associated with worse cancer prognosis and increased mortality. […] circadian misalignment, such as that experienced by “shift workers,” has been shown to be associated with an increased incidence of several malignancies, including breast, colorectal, and prostate cancer, consistent with the increasing recognition of the role of clock genes in metabolic processes […] This volume […] review[s] current state-of-the-art studies on sleep, obesity, and cancer, with chapters focusing on molecular and physiologic mechanisms by which sleep disruption contributes to normal and abnormal physiology, related clinical consequences, and future research needs for laboratory, clinical, and translational investigation.”

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I’m currently reading this book. I probably shouldn’t be reading it; I realized a couple of weeks ago that if I continue at the present rate I’ll get to something like 100 books this year, and despite some of these books being rather short and/or fiction books I don’t think this is a healthy amount of reading. It’s probably worth noting in this context that despite the fact that the number of ‘books read’ is now much higher than it used to be, I incidentally am far from sure if I actually read any more stuff now than I did in the past; it may just be that these things have become easier to keep track of as I now read a lot more books and a lot less ‘unstructured online stuff’. It’s not a new problem, but it’s getting rather obvious.

But anyway I’m reading the book, and although it may not be a good way for me to spend my time I am at least learning some stuff I did not know. The book is a standard Springer publication, with 11 chapters each of which deals with a specific topic of interest (a few examples: ‘Effects of Sleep Deficiency on Hormones, Cytokines, and Metabolism’, ‘Biomedical Effects of Circadian Rhythm Disturbances’, and ‘Shift Work, Obesity, and Cancer’). I’ve added some observations from the book below as well as some comments – I’ll probably post another post about the book later on once I’ve finished reading it. The very short version is that insufficient sleep may be quite bad for you.

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“Insomnia, identified by complaints of problems initiating and/or maintaining sleep, is common, especially among women. Insomnia is often associated with a state of hyperarousal and has been linked to increased risk of depression, myocardial infarction, and cardiovascular mortality [15]. Relative risks for cardiovascular disease for insomnia have been estimated to vary from 1.5 to 3.9; a dose-dependent association between frequency of insomnia symptoms and acute myocardial infarction has been demonstrated [16]. Insomnia may be particularly problematic at certain times in the lifespan, especially in the perimenopause period and in association with acute life stresses, such as loss of a loved one. The occurrence of insomnia during critical periods, such as menopause, may contribute to increased cardiometabolic risk factors at those times. Short sleep duration may occur secondary to a primary sleep disorder or secondary to behavioral/social issues. Regardless of etiology, short sleep duration has been associated with increased risk of obesity, weight gain, diabetes, cardiovascular disease, and premature mortality [17,18].”

“Sleep is characterized not only by its presence or absence (and timing) but by its quality. Sleep is composed of distinct neurophysiological stages […] associated with differences in arousal threshold, autonomic and metabolic activity, chemosensitivity, and hormone secretion [2] […] Each sleep stage is characterized by specific patterns of EEG activity, described by EEG amplitude (partly reflecting the synchronization of electrical activity across the brain) and EEG frequency. Lighter sleep (stages N1, N2) displays relatively low-amplitude and high-frequency EEG activity, while deeper sleep (slow-wave sleep, N3) is of higher amplitude and lower frequency. Stages N1, N2, and N3 comprise non-rapid eye movement (REM) sleep (NREM). In contrast, rapid eye movement (REM) sleep is a variable frequency, low-amplitude stage, in which rapid eye movements occur and muscle tone is low. […] In adults, over the course of the night, NREM and REM sleep cycles recur approximately every 90 min, although their composition differs across the night: early cycles typically have large amounts of N3, while later cycles have large amounts of REM. The absolute and percentage times in given sleep stages, as well as the pattern and timing of progression from one stage to another, provide information on overall sleep architecture and are used to quantify the degree of sleep fragmentation. Sleep characterized by frequent awakenings, arousals, and little N3 is considered to be lighter or non-restorative and contributes to daytime sleepiness and impaired daytime function. Higher levels of N3 are thought to be “restorative.””

“The circadian rhythm changes with age and one important change is a general shift to early sleep times (advanced sleep phase) with advancing age. While teenagers and college students have a tendency due to both intrinsic rhythm and external pressures to have later bedtimes, this starts to wane in young adulthood. This phase advance to an earlier sleep time has been referred to as “an end to adolescence” and happens at a younger age for women than for men [60]. […] During the transition from adolescence to adult, several changes occur to the sleep architecture. Most notably is the significant reduction in stage N3 sleep by approximately 40 % as the child progresses through the teenage years […] This means that other stages of NREM (N1 and N2) take up more of the sleep time. Functionally this translates to the child having lighter sleep during the night and therefore is easier to arouse and awaken. […] The sleep architecture of young adults is […] in a 90-min cycle with all sleep stages represented. The amount of stage N3 sleep continues to reduce at this time, at a rate of approximately 2 % per decade up to age 60 years. There is also a smaller reduction in REM sleep during early and mid-adulthood. Once through puberty and into the 20s, most adults sleep approximately 7–8 h per night. This remains relatively constant through mid-adulthood. Young adults may still sleep a bit longer, 8–9 h for a few years. The need for sleep does not change as people progress to mid-adulthood, but the ability to maintain sleep may be affected by medical conditions and environmental influences. […] although average sleep duration does not change over adulthood, there is a large degree of inter- and intraindividual variability in sleep duration. Individuals who are consistently short sleepers (e.g., <6 h per night) and long sleepers (>9 h per night) and who demonstrate high between-day variability in sleep duration are at increased risk for weight gain, diabetes, and other metabolic dysfunction and chronic disease.”

“Nine retrospective studies have indicated that shift work might be associated with a higher risk of breast cancer, including three studies in Denmark, three studies in Norway, two studies in France, and one study in the United States. […] Three of four prospective studies have provided evidence in favor of an association between shift work and breast cancer. […] evidence for a relation between shift work and prostate cancer is very limited, both by the small number of studies and by major limitations involved in those studies that have been conducted”

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The increased risk of breast cancer may well be quite significant not only in the statistical sense of the word, but also in the normal, non-statistical, sense of the word; for example the estimated breast cancer odds ratio of Norwegian nurses who’d worked 30+ years of nightwork, compared to those who hadn’t done any nightwork, was 2.21 (1.10-4.45) – and that study involved more than 40.000 nurses. Another study dealing with the same cohort found that the nurses who’d worked more than five years with schedules involving more than 5 consecutive night shifts also had an elevated risk of breast cancer (odds ratio: 1.6 (1.0-2.4)). It’s noteworthy that many of the studies on this topic according to the authors suffer from identification problems which if anything are likely to bias the estimates towards zero. As you should be able to tell from the reported CIs above, the numbers are somewhat uncertain, but that doesn’t exactly make them irrelevant or useless; roughly 1 in 8 women at baseline can expect to get breast cancer during their lifetime (link), so an odds ratio of, say, 2 is actually a really big deal – and even if we don’t know precisely what the correct number is, the risk certainly seems to be high enough to warrant some attention. One mechanism proposed in the shift work chapter is that the altered sleep patterns of shift workers lead to weight gain, and that weight gain is then part of the explanation for the increased cancer risk. I’ve read aboutandwrittenabout the obesity-cancer link before so this is stuff I know a bit about, and that idea seems far from far-fetched to me. And actually it turns out that the link between shift work and weight gain seems significantly stronger than does the link between shift work and cancer – which is precisely what you’d expect if it’s not the altered sleep patterns per se which increase cancer risk, but rather the excess adipose tissue which so often follows in its wake:

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“Numerous epidemiologic studies have examined the association between shift work and obesity in various different countries. Most of these studies have utilized existing data from employment records in particular companies, which provide convenient but typically limited information on shift work and health-related variables because this information was not originally collected for research purposes. As a result, many of these studies have methodological issues that potentially limit the interpretation of their results. Still, 22 of 23 currently published studies found some evidence that obesity is significantly more common among individuals with shift work experience compared to those without such experience [36–57]; only one study did not identify a possible link [58]. […] many analyses of shift work and obesity lack adjustment for potentially important confounding variables (e.g., other health and lifestyle factors), and therefore prospective studies with more extensive information on these variables have provided critical insight. Four such prospective studies have been conducted, all of which indicate that individuals who perform shift work tend to experience significant weight gain over time — including two studies in Japan, one study in Australia, and one study in the United States. […] in the largest and most detailed analysis to date, each 5-year increase in rotating shift work experience was associated with a gain of 0.17 kg/m2 in body mass index (95 % CI = 0.14–0.19) or 0.45 kg in weight (95 % CI = 0.38–0.53), among 107,663 women who were followed over 18 years in the US Nurses’ Health Study 2 [57]. Statistical models were adjusted extensively for age, baseline body mass index, alcohol intake, smoking, physical activity, and other health and lifestyle indicators.”

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A major problem with the ‘shift work -> obesity -> cancer’ -story is however that the identified weight gain effect sizes seem really small (one pound over five years is not very much, and despite how dangerous excess adipose tissue may be, those kinds of weight differences certainly aren’t big enough to explain e.g. the breast cancer odds ratio of 1.6 mentioned above) – the authors don’t spell this out explicitly, but it’s obvious from the data. It may be slightly misleading to consider only the average effects, as some women may be more sensitive than others to these effects and outliers may be important, but not that misleading; I don’t think it’s plausible to argue that this is all about body mass. In the few studies where they have actually looked at obesity as a potential effect modifier, the results have not been convincing:

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“Although it is possible that obesity predicts both shift work and cancer risk — as would be required for obesity to be a potential confounding factor of this relation — it is probably more likely that shift work predicts obesity, in addition to obesity being a risk factor for many types of cancer. This scenario is suggested by the prospective studies of shift work and obesity described above; that is, obesity is a stronger candidate for effect modification than confounding of the association between shift work and cancer, as shift work appears to influence the risk of obesity over time. Yet, only three prior studies have conducted stratified analyses based on obesity status to evaluate the possibility of effect modification. Two of these studies focused on shift work and breast cancer, but they found no evidence of effect modification by obesity [24,26]; a third study of shift work and endometrial cancer did identify obesity as an effect modifier [32]. […] Clearly, additional studies need to carefully consider the role of body mass index—a possible confounding factor, but more likely effect modifying factor—in the association between shift work and obesity.”

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I should make clear that although it makes sense to assume that obesity is a potentially major variable in the sleep-cancer risk relation, there are a lot of other variables that likely play a role as well, and that the book actually talks about these things as well even though I haven’t covered them here:

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“Although the exact mechanisms by which various sleep disorders may affect the initiation and progression of cancer are largely unknown, disruption of circadian rhythm, pervasive in individuals with sleep disorders, is thought to be the underlying denominator linking sleep disorders, as well as shift work and sleep deprivation, to cancer. The circadian system synchronizes the host’s daily cyclical physiology from gene expression to behavior [55]. Disruption of circadian rhythm may influence tumorigenesis through a number of mechanisms, including disturbed homeostasis and metabolism (details provided in Chap. 2), suppression of melatonin secretion (details provided in Chap. 3), intermittent hypoxia and oxidative stress (details provided in Chap. 5), reduced capacity in DNA repair, and energy imbalance.”

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The obesity link relates to a few of these, but there’s a lot of other stuff going on as well. I may talk about some of those things later – I thought chapter 7 was quite interesting, so I’ve ended up talking quite a bit about that chapter in this post, and neglected to cover some of the earlier stuff covered in the book.

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